Thyroid Disease in Pregnancy Chantarojanasiri T. ,MD.

OUTLINE Normal physiology& changes during pregnancy Hyperthyroid Hypothyroid Postpartum thyroid disease Thyroid cancer Euthyroid with autoimmune thyroid disease Practice guidelines

Normal physiology The hypothalamic pituitary axis Thyrotropin-releasing hormone (TRH) Produced in a tonic fashion in the paraventricular nucleus of the hypothalamus. TSH has an α and β subunit;β subunit confers specificity. TSH secretion regulated by negative feedback from circulating thyroid hormone, dopamine, and somatostatin. TSH then stimulates the thyroid gland to produce, as well as secrete, thyroxine(T4) and triiodothyronine (T3).

The rate-limiting step is iodide trapping mediated by TSH. nonpregnant state, 80 mg/d to 100 mg/d of iodine taken up 20% of the intake is cleared by the thyroid gland; remainder renally

Physiologic adaptation during pregnancy increase in thyroid-binding globulin secondary to an estrogenic stimulation of TBG synthesis and reduced hepatic clearance of TBG ;two to threefold levels of bound proteins, total thyroxine, and total triiodothyronine are increased and resin triiodothyronine uptake (RT3U) is decreased begins early in the first trimester, plateaus during midgestation, and persists until shortly after delivery decrease in its hepatic clearance,estrogen-induced sialylation free T4 and T3 increase slightly during the first trimester in response to elevated hCG. decline to nadir in third trimester

human chorionic gonadotropin (hCG) intrinsic thyrotropic activity begins shortly after conception, peaks around gestational week 10,declines to a nadir by about week 20 directly activate the TSH receptor partial inhibition of the pituitary gland (by cross-reactivity of the α subunit) transient decrease in TSH between Weeks 8 and 14 mirrors the peak in hCG concentrations 20% of normal women, TSH levels decrease to less than the lower limit of normal

hCG TSH

reduction in plasma iodide A decrease in basal TSH of 0.1 mU/L was observed for every 10,000 IU/L increment in hCG reduction in plasma iodide fetal :monodeiodinase types II and III in the placenta increased maternal glomerular filtration rate-- increased renal clearance of iodide throughout pregnancy transplacental passage of T4 and iodide and placental metabolism of iodothyronines stimulate the maternal thyroid ; depleting the maternal circulation of thyroid hormone and its precursors

Hypothyroid;25% to 47% average dosage increase during pregnancy increased serum thyroid stimulating hormone (TSH) and thyroglobulin concentrations, relative hypothyroxinemia, and occasional goiter formation Esp. from area with borderline iodine sufficiency associated with increase in thyroid gland size in 15%

EFFECTS OF PREGNANCY ON THYROID PHYSIOLOGY Physiologic Change Thyroid-Related Consequences ↑ Serum thyroxine-binding globulin ↑ Total T4 and T3; ↑ T4 production ↑ Plasma volume ↑ T4 and T3 pool size; ↑ T4 production; ↑ cardiac output D3 expression in placenta and (?) uterus ↑ T4 production First trimester ↑ in hCG ↑ Free T4; ↓ basal thyrotropin; ↑ T4 production ↑ Renal I- clearance ↑ Iodine requirements ↑ T4 production; fetal T4 synthesis during second and third trimesters   ↑ Oxygen consumption by fetoplacental unit, gravid uterus, and mother ↑ Basal metabolic rate; ↑ cardiac output

Hyperthyroidism and pregnancy 0.2% of pregnancies prevalence 0.1% to 0.4%, with 85% Graves’ disease Single toxic adenoma, multinodular toxic goiter, and subacute thyroiditis gestational trophoblastic disease,viral thyroiditis and tumors of the pituitary gland or ovary (struma ovarii) TSH is depressed and fT4 and fTI are increased. The RT3U that normally is decreased in pregnancy is increased in hyperthyroidism.

Hyperthyroidism and pregnancy serum TSH value <0.01 mU/L and also a high serum free T4 value may be difficult to determine the cause thyroid radionuclide imaging is contraindicated in pregnant women. Measurement of thyrotropin receptor antibody (thyroid stimulating immunoglobulins)  Graves' disease during pregnancy transient hyperthyroidism in hyperemesis gravidarum and gestational transient thyrotoxicity (GET)

Hyperthyroidism and pregnancy Severe maternal hyperthyroidism increased risk of stillbirth preterm delivery intrauterine growth restriction Preeclampsia heart failure spontaneous abortion Fetal thyroid hyperfunction or hypofunction caused by TSHRAbs Fetal goiter from excessive antithyroid drug treatment Neonatal thyrotoxicosis Increased perinatal and maternal mortality Decreased IQ of offspring because of excessive use of antithyroid drugs

Transient hyperthyroidism during pregnancy & gestational transient thyrotoxicity (GET) hyperemesis gravidarum severe nausea and vomiting leading to a 5% loss of body weight, dehydration, and ketosis. absence of goiter and ophthalmopathy, and absence of the common symptoms and signs of hyperthyroidism higher serum hCG and estradiol concentrations 60% have a subnormal serum TSH level (< 0.4 mU/L),50% have an elevated serum free T4 concentration Severity positively correlated with maternal free T4 levels but not to thyroid function. 12% elevated free T3 index believed to be related to hCG stimulation of the thyroid gland Normalization of T4 levels by midgestation. Treatment is supportive care

GET first trimester related to hCG stimulation of the thyroid gland symptoms of hyperthyroidism and elevated free T4 levels. The thyroid gland usually is not enlarged resolution of symptoms parallels the decline in hCG levels usually resolves spontaneously by 20 weeks’ gestation beyond 20 weeks,repeat evaluation for other causes

Trophoblastic hyperthyroidism hydatidiform mole (molar pregnancy) & choriocarcinoma. high serum hCG concentrations and abnormal hCG isoforms 55 to 60 percent had clinically evident hyperthyroidism normal thyroid gland and few symptoms of thyroid hormone excess. some :findings of hyperthyroidism and a diffuse goiter ophthalmopathy is not present Nausea and vomiting may predominate

subclinical hyperthyroidism associated with osteoporosis, cardiovascular morbidity, and progression to overt thyrotoxicosis and thyroid failure. not associated with adverse pregnancy outcomes does not warrant treatment.

Graves’ disease 95% of thyrotoxicosis during pregnancy. activity level fluctuate during gestation, with exacerbation during the first trimester gradual improvement during the latter half. exacerbation shortly after delivery clinical scenarios. stable Graves’ disease receiving thionamide therapy with exacerbation during early pregnancy. in remission with a relapse of disease. without prior history diagnosed with Graves’ disease de novo during pregnancy.

Graves’ disease Diagnosis difficult :hypermetabolic symptoms in normal pregnancy thyroid examination: goiter (with or without bruit) suppressed serum TSH level and usually elevated free and total T4 serum concentrations. TSH receptor antibodies complications related to the duration and control of maternal hyperthyroidism autoantibodies mimic TSH can cross the placenta and cause neonatal Graves’ disease

Graves’ disease Pregnancy outcome preterm labor preeclampsia untreated (88%)/partially treated(25%) /adequately treated (8%) [ preeclampsia untreated twice stillbirth untreated (50%) /partially treated (16%) /adequately treated (0%) small for gestational age congenital malformations unrelated to thionamide therapy Mother may have thyroid-stimulating hormone-binding inhibitory immunoglobulin (TBII), cause transient neonatal hypothyroidism fetal bradycardia, goiter,and growth restriction

Graves’ disease Neonatal thyrotoxicosis : 1% of infants occur in euthyroid mother or has had surgical or radioactive 131I treatments before pregnancy fetal ultrasound to exclude evidence of fetal thyrotoxicosis (eg, an anterior fetal neck mass) or fetal tachycardia. fetal goiter, advanced bone age, poor growth, and craniosynostosis, Cardiac failure and hydrops Fetal blood sampling — Fetal blood for thyroid function tests by percutaneous umbilical vein sampling after 20 weeks of gestation High maternal TSH receptor-stimulating antibody levels Fetal signs suggestive of thyroid disease History of a prior baby with hyperthyroidism

Thyroid storm obstetric emergency extreme metabolic state 10% of pregnant women with hyperthyroidism high risk of maternal cardiac failure. fever, change in mental status, seizures, nausea, diarrhea, and cardiac arrhythmias. inciting event (eg, infection, surgery, labor/delivery) and a source of infection treatment immediately, even if serum free T4, free T3, and TSH levels are not known. untreated thyroid storm can be shock, stupor, and coma.

Guidelines for clinical management of maternal hyperthyroidism during pregnancy 1. Use the lowest dosage of thionamide (preferably PTU) to maintain maternal total T4 concentrations in the upper one third of normal to slightly elevated range for pregnancy. Normal range of total T4 during pregnancy is estimated to be 1.5 times the nonpregnant state 2. Monitor maternal total T4 serum concentration every 2–4 weeks, and titrate thionamide as necessary. Monitoring serum TSH may become useful later. Shane O. LeBeau, Endocrinol Metab Clin N Am 35 (2006) 117–136

Guidelines for clinical management of maternal hyperthyroidism during pregnancy 3. Measure TSH receptor antibodies (thyroid-stimulating immunoglobulins or TSH receptor binding inhibitory immunoglobulins) at 26–28 weeks to assess risk of fetal/neonatal hyperthyroidism. TSH receptor antibody measurement is crucial in hypothyroid levothyroxine-treated women with a prior history of Graves’ disease, who do not appear thyrotoxic. 4. Perform fetal ultrasound at weeks 26–28 to assess potential fetal response to thionamide treatment and effect of TSH receptor antibodies on fetal thyroid function

Guidelines for clinical management of maternal hyperthyroidism during pregnancy 5. Consider thyroidectomy if persistently high doses of thionamide (PTU > 600 mg/d or MMI > 40 mg/d) are required,or if the patient cannot tolerate thionamide therapy. 6. β-Adrenergic blocking agents and low doses of iodine may be used perioperatively to control hyperthyroid state. 7. Check fetal cord blood at delivery for TSH and T4.

Treatment Thionamides propylthiouracil (PTU) and methimazole(MMI) Both cross the placenta with equal transfer kinetics. Both can cause fetal goiter and hypothyroidism, usually mild and transient & dose-dependent median time to normalization of maternal thyroid function 7 weeks with PTU and 8 weeks with MMI PTU more highly bound to albumin theorize that MMI crosses the placenta in higher concentrations

Treatment Thionamides maternal :rash rare birth defects in MMI: aplasia cutis, choanal atresia,esophageal atresia, and minor dysmorphic features Low thyroid function at birth ½ neonates whose mothers received PTU or MMI and had serum T4 concentrations within the normal (non-pregnant) range normal IQ scores Graves’ disease may ameliorate thionamide discontinued in 30% during the final weeks fall in serum TSH receptor-stimulating antibody concentrations and a rise in TSH receptor-blocking antibodies. Graves' hyperthyroidism can worsen postpartum do not recommend the use of T4 with thionamide therapy during pregnancy.

Treatment β-Adrenergic blockers Iodides weaned as soon as the hyperthyroidism is controlled occasional cases of neonatal growth restriction, hypoglycemia, respiratory depression, and bradycardia increased frequency of first-trimester miscarriages avoiding in the first trimester Iodides past reports of neonatal hypothyroidism after exposure to iodine low-dose potassium iodide may be considered Preparation for thyroidectomy thionamide-intolerant patients refusing surgery.

Treatment Surgery Subtotal thyroidectomy : persistently high dosages of thionamides (PTU > 600 mg/d, MMI > 40 mg/d) are required to control maternal disease allergic or intolerant of both thionamides noncompliant with medical therapy compressive symptoms second trimester, before gestational week 24 prepared with a β-adrenergic blocking agent and a 10- to 14-day course of potassium iodide

Treatment Radioactive iodine therapy Nursing contraindicated fetal thyroid gland begins to concentrate iodine after gestational week 10, Fetal thyroid tissue is present by 10 to 12 weeks predisposing to congenital hypothyroidism Nursing Breast feeding in mothers taking PTU or MMI is safe Thyroid function in newborn infants is unaffected PTU is preferred because it is less concentrated in breast milk

Hypothyroidism in pregnancy elevated serum TSH concentration:2.5% of pregnancies In iodine-sufficient environment Hashimoto’s thyroiditis prior radioactive iodine treatment surgical ablation of Graves’ disease less common causes: overtreatment of hyperthyroidism with thionamides, transient hypothyroidism owing to postpartum thyroiditis, medications that alter the absorption or metabolism of levothyroxine, and pituitary/hypothalamic disease)

Hypothyroidism in pregnancy diagnosis Symptoms masked by the hypermetabolic state of pregnancy. 20% to 30% overt hypothyroidism develop symptoms weight gain, lethargy, decrease in exercise capacity, and intolerance to cold,constipation, hoarseness, hair loss, brittle nails, dry skin, goiter, or delay in the relaxation phase of the deep tendon reflexes Elevated serum TSH concentration Central hypothyroidism do not manifest an elevated serum TSH level

Hypothyroidism in pregnancy Pregnancy outcome depends on the severity of disease and adequacy of treatment Gestational hypertension in overtly hypothyroid women (36%) vs subclinical disease (25%) or the general population (8%) Overt hypothyroid vs subclinical disease, increased use of cesarean section because of fetal distress placental abruption, anemia, andpostpartum hemorrhage increased rates of miscarriage, preeclampsia,placental abruption, growth restriction, prematurity and stillbirths fetuses are at risk for impaired neurologic development low-birth-weight neonates

Hypothyroidism in pregnancy TSH can be elevated with or without suppressed levels of free T4. antithyroid autoantibodies (eg, antithyroglobulin, antithyroid peroxidase) are present elevated creatine phosphokinase, cholesterol, and liver function tests 5% to 8% prevalence of hypothyroidism in type I diabetes mellitus and women who have type I diabetes have a 25% risk of developing postpartum thyroid dysfunction

Causes of hypothyroidism Worldwide, the most common is iodine deficiency. impaired neurologic development; severe mental retardation, deafness, muteness, and pyramidal or extrapyramidal syndromes; Hashimoto’s thyroiditis Idiopathic hypothyroidism; atrophic thyroid gland and absent antithyroid antibodies. 131I treatment for Graves’ disease and thyroidectomy Drugs interfere with the metabolism of thyroid hormones

Subclinical hypothyroidism normal free T4 level elevated TSH above the upper limit of reference range (4.5–10.0mIU/L) thresholds based on gestational age. TSH in the first half of pregnancy is 3.0 mIU/L prevalence of subclinical hypothyroidism 2–5% increased risk of placental abruption and preterm birth important to monitor TSH and free T4 levels. 2–5% progress to overt hypothyroidism each year

Isolated maternal hypothyroxinemia normal TSH free T4 below 0.86 ng/dl. In the first half of pregnancy, prevalence 1.3%. not associated with adverse perinatal outcome

Guidelines for clinical management of maternal hypothyroidism during pregnancy 1. Check serum TSH level as soon as pregnancy is confirmed. 2. For newly diagnosed hypothyroid women, initial levothyroxine dosage is based on severity of hypothyroidism. For overt hypothyroidism, administer 2 mcg/kg/d. If TSH is < 10 mU/L, initial dose of 0.1 mg/d may be sufficient. 3. For previously diagnosed hypothyroid women, monitor serum TSH every 3–4 weeks during first half of pregnancy and every 6 weeks thereafter. 4. Adjust levothyroxine dosage to maintain serum TSH ≤ 2.5 mU/L. 5. Monitor serum TSH and total T4 levels 3–4 weeks after every dosage adjustment. When levothyroxine dosage achieves equilibrium, resume monitoring TSH alone Shane O. LeBeau, Endocrinol Metab Clin N Am 35 (2006) 117–136

Treatment 6. Levothyroxine ingestion should be separated from prenatal vitamins containing iron, iron and calcium supplements,and soy products by at least 4 hours to ensure adequate absorption. 7. After delivery, reduce levothyroxine to prepregnancy dosage, and check serum TSH in 6 weeks adjusting levothyroxine 1. TSH < 10 mU/L, increase 0.05 mg/d. 2. TSH =10–20 mU/L, increase 0.075 mg/d. 3. TSH > 20 mU/L, increase 0.1 mg/d. normal range for total T4 concentrations during pregnancy is 1.5 times the nonpregnant iodine :prenatal vitamin 220 mg/day

Postpartum thyroid disease Postpartum thyroiditis Dx: documenting abnormal TSH (elevated or suppressed) levels during the first year postpartum in the absence of positive TSI or a toxic nodule hypo- or hyperthyroidism classic presentation : transient hyperthyroid phase that occurs 6 weeks to 6 months postpartum followed by a hypothyroid phase that lasts for up to 1 year postpartum

Postpartum thyroiditis autoimmune disorder with a self-limited hyperthyroid phase within one year after parturition. Presentations Transient hyperthyroidism alone Transient hypothyroidism alone Transient hyperthyroidism followed by hypothyroidism and then recovery. can also occur after spontaneous or induced abortion 3 to 16 percent higher, up to 25 percent, in women with type 1 diabetes mellitus ,and in women with positive antithyroid antibodies (normal thyroid function)

Postpartum thyroiditis like painless thyroiditis variant form of chronic autoimmune thyroiditis (Hashimoto's thyroiditis). high serum concentrations of anti-peroxidase antibodies many eventually become hypothyroid or have a goiter high serum antithyroid antibody concentrations early in pregnancy decline later (as immunologic tolerance increases during pregnancy) rise again after delivery subclinical thyroid autoimmune disease early in pregnancy and soon after Progression to permanent hypothyroidism related to higher TSH concentrations and the antiperoxidase antibody titer maternal age and female sex of the infant Postpartum thyroiditis is likely to recur after subsequent pregnancies

distinguished from Graves' hyperthyroidism, hyperthyroidism in postpartum thyroiditis is usually mild (both clinically and biochemically), thyroid enlargement is minimal Graves' ophthalmopathy is absent. by reevaluation in three to four weeks: postpartum thyroiditis improved lymphocytic hypophysitis, TSH normal or low, low free T4 postpartum thyroiditis, TSH elevated with decreased FT4.

Postpartum thyroiditis antithyroids :no role. Hypothyroid :may require treatment and some significant rate of residual hypothyroidism Recommend:maintain thyroxine until childbearing is complete, with an attempt to wean off medication 1 year after the last delivery Postpartum--signs/symptoms of thyroid dysfunction symptoms mimic normal postpartum changes TSH, free T4, and antithyroid antibodies levels postpartum depression and postpartum thyroiditis

Postpartum Graves’ disease 60% Graves’ disease in the reproductive years; postpartum onset euthyroid patients with Graves’ disease with TSI increased risk of developing recurrent Graves’ disease if antithyroid medication was withheld TSIs differentiate postpartum Graves’ disease from postpartum thyroiditis with a hyperthyroid component.

Thyroid cancer Thyroid tumors ;most common endocrine neoplasms. thyroid cancer accounts for 1% of all cancers. ¾ women; 1/2 reproductive years. biopsy ,Serum TSH and free T4 levels,ultrasonography & Fine needle aspiration Radionucleotide scanning is contraindicated during pregnancy malignant or suspicious for papillary cancer, surgery at the earliest safe period no evidence that pregnancy causes a reactivation of thyroid cancer or that exposure to radioactive iodine poses a risk to future pregnancies maintained on thyroid replacement therapy with monitoring of TSH and free T4 levels every 8 weeks.

Euthyroidism with autoimmune thyroid disease increased risk for spontaneous miscarriage, subclinical hypothyroidism, and postpartum thyroiditis Increase in serum TSH levels most normal presence of antithyroid antibodies lack of thyroidal reserve in response to the stimulatory effects of pregnancy.

Euthyroidism with autoimmune thyroid disease recommend initiating levothyroxine therapy in women with antithyroid antibodies before pregnancy TSH level greater than 2.5 mU/L. Serum TSH should be monitored throughout pregnancy in all antithyroid antibody–positive women maintain the TSH concentration at 2.5 mU/L or less.

1. HYPOTHYROIDISM AND PREGNANCY: MATERNAL AND FETAL ASPECTS CLINICAL PRACTICE GUIDELINE Management of Thyroid Dysfunction during Pregnancy and Postpartum: An Endocrine Society Clinical Practice Guideline 1. HYPOTHYROIDISM AND PREGNANCY: MATERNAL AND FETAL ASPECTS 1.1.1. maternal hypothyroidism should be avoided.Targeted case finding is recommended at the first prenatalvisit or at diagnosis of pregnancy 1.1.2. If hypothyroidism diagnosed before pregnancy, adjust preconception T4 dose to reach a TSH ≤2.5 U/ml before pregnancy. 1.1.3. T4 dose incremented by 4–6 wk gestation and 30–50% increase in dosage. 1.1.4. If overt hypothyroidism is diagnosed during pregnancy, thyroid function tests should be normalized as rapidly as possible. The T4 dosage should be titrated to rapidly ,maintain serum TSH ≤ 2.5 U/ml in the first trimester (or 3 U/ml in the second and third trimesters) or to trimester-specific normal TSH ranges. Thyroid function tests remeasured within 30–40 d. Abalovich et al. • Guideline: Thyroid Dysfunction during and after Pregnancy J Clin Endocrinol Metab, August 2007, 92(8) (Supplement):S1–S47

1.1.6. Subclinical hypothyroidism ;associated with an 1.1.5. Women with thyroid autoimmunity who are euthyroid in the early stages of pregnancy are at risk of developing hypothyroidism and should be monitored for elevation of TSH above the normal range 1.1.6. Subclinical hypothyroidism ;associated with an adverse outcome for both the mother and offspring. T4 treatment - improve obstetrical outcome but has not been proved to modify long-term neurological development in the offspring. Recommends T4 replacement in women with subclinical hypothyroidism. 1.1.7. After delivery, most hypothyroid women need a decrease in the T4 dosage they received during pregnancy

2. MANAGEMENT OF MATERNAL HYPERTHYROIDISM: MATERNAL (A) AND FETAL (B) ASPECTS 2.1.a.1. subnormal serum TSH hyperthyroidism must be distinguished from both normal physiology during pregnancy and hyperemesis gravidarum Differentiation of Graves’ disease from gestational thyrotoxicosis by evidence of autoimmunity, a goiter, and presence of TRAb. 2.1.a.2. For overt hyperthyroidism due to Graves’ disease or hyperfunctioning thyroid nodules, ATD therapy should be either initiated (for those with new diagnoses) or adjusted (for those with a prior history) maintain the maternal thyroid hormone levels for free T4 in the upper nonpregnant reference range. 2.1.a.3. methimazole may be associated with congenital anomalies, propylthiouracil should be used as a first-line drug, especially during first-trimester organogenesis. Methimazole may be prescribed if propylthiouracil is not available or if a patient cannot tolerate or has an adverse response to propylthiouracil

2.1.a.4. Subtotal thyroidectomy for maternal Graves’ disease if 1) a patient has a severe adverse reaction to ATD therapy, 2)persistently high doses of ATD are required 3) a patient is not adherent to ATD therapy and has uncontrolled hyperthyroidism. optimal timing of surgery is in the second trimester. 2.1.a.5. no evidence that treatment of subclinical hyperthyroidism improves pregnancy outcome 2.1.b.1 TRAb (either TSH receptor-stimulating or –binding antibodies) freely cross the placenta and can stimulate the fetal thyroid. These antibodies should be measured before pregnancy or by the end of the second trimester in mothers with current Graves’ disease, with a history of Graves’ disease and treatment with 131I or thyroidectomy, or with a previous neonate with Graves’ disease. Women who have a negative TRAb and do not require ATD have a very low risk of fetal or neonatal thyroid dysfunction.

2.1.b.2. 131I should not be given to a woman who is or may be pregnant. radiation danger to the fetus, including thyroid destruction if treated after the 12th week of gestation. There are no data for or against recommending termination of pregnancy after 131I exposure 2.1.b.3. In women with elevated TRAb or in women treated with ATD, fetal ultrasound should be performed to look for evidence of fetal thyroid dysfunction growth restriction, hydrops, presence of goiter, or cardiac failure. 2.1.b.4. Umbilical blood sampling should be considered only if the diagnosis of fetal thyroid disease is not reasonably certain from the clinical data and if the information gained would change the treatment. 2.1.b.5. All newborns of mothers with Graves’ disease should be evaluated for thyroid dysfunction and treated if necessary

3. GESTATIONAL HYPEREMESIS AND HYPERTHYROIDISM 3.1. Thyroid function tests should be measured in all patients with hyperemesis gravidarum (5% weight loss, dehydration, and ketonuria) 3.2. Few women with hyperemesis gravidarum will require ATD treatment. Overt hyperthyroidism believed due to coincident Graves’ disease should be treated with ATD. Gestational hyperthyroidism with clearly elevated thyroid hormone levels (free T4 above the reference range or total T4 150% of top normal pregnancy value and TSH 0.1 U/ml) and evidence of hyperthyroidism may require treatment as long as clinically necessary 4. AUTOIMMUNE THYROID DISEASE AND MISCARRIAGE 4.1. universal screening for antithyroid antibodies and possible treatment cannot be recommended at this time.

5. THYROID NODULES AND CANCER 5.1. Fine-needle aspiration (FNA) cytology should be performed for thyroid nodules larger than 1 cm. Ultrasound-guided FNA minimizing inadequate sampling. 5.2. When nodules are discovered in the first or early second trimester to be malignant on cytopathological analysis or exhibit rapid growth, surgery should be offered in the second trimester before fetal viability. For papillary cancer or follicular neoplasm without evidence of advanced disease prefer to wait until the postpartum period for definitive surgery reassured that most well differentiated thyroid cancers are slow growing surgical treatment soon after delivery is unlikely to adversely affect prognosis

5.3. administer thyroid hormone to achieve a suppressed but detectable TSH in pregnant women with a previously treated thyroid cancer or an FNA positive for or suspicious for cancer and those who elect to delay surgical treatment until postpartum. High-risk patients benefit from a greater degree of TSH suppression free T4 or total T4 levels should ideally not be increased above the normal range for pregnancy. 5.4. RAI administration with 131I should not be given to women who are breastfeeding. pregnancy should be avoided for 6 months to 1 yr in women with thyroid cancer who receive therapeutic RAI doses to ensure stability of thyroid function and confirm remission of thyroid cancer.

6. IODINE NUTRITION DURING PREGNANCY 6.1. Women of childbearing age ; average iodine intake 150 g/d. pregnancy and breastfeeding women should increase intake to 250 g 6.2. Iodine intake during pregnancy and breastfeeding should not exceed twice the daily recommended nutritional intake for iodine, i.e. 500 g iodine per day 6.3. To assess the adequacy of the iodine intake during pregnancy in a population, urinary iodine concentration should be measured in a cohort of the population. Urinary iodine concentration should ideally range between 150 and 250 g/liter. 6.4. To reach the daily recommended nutrient intake for iodine, multiple means must be considered, tailored to the iodine intake level in a given population. 1) countries with iodine sufficiency and/or with a well established universal salt iodization (USI) program, 2) countries without a USI program or an established USI program where the coverage is known to be only partial, and finally 3) remote areas with no accessible USI program and difficult socioeconomic conditions.

7. POSTPARTUM THYROIDITIS 7.1. There are insufficient data to recommend screening of all women for PPT. 7.2. Women known to be thyroid peroxidase antibody positive should have a TSH performed at 3 and 6 months postpartum 7.3. The prevalence of PPT in women with type 1 diabetes is 3-fold greater than in the general population. Postpartum screening (TSH determination) is recommended for women with type 1 diabetes mellitus at 3 and 6 months postpartum 7.4. Women with a history of PPT have a markedly increased risk of developing permanent primary hypothyroidism in the 5- to 10-yr period after the episode of PPT. An annual TSH level should be performed in these women.

7.5. Asymptomatic women with PPT who have a TSH above the reference range but less than 10 U/ml and who are not planning a subsequent pregnancy do not necessarily require intervention but should be remonitored in 4–8 wk. Symptomatic women and women with a TSH above normal and who are attempting pregnancy should be treated with levothyroxine. 7.6. There is insufficient evidence to conclude whether an association exists between postpartum depression and either PPT or thyroid antibody positivity (in women who did not develop PPT). women with postpartum depression should be screened for hypothyroidism and appropriately treated.

8. SCREENING FOR THYROID DYSFUNCTION DURING PREGNANCY 1. Women with a history of hyperthyroid or hypothyroid disease, PPT, or thyroid lobectomy. 2. Women with a family history of thyroid disease. 3. Women with a goiter. 4. Women with thyroid antibodies (when known). 5. Women with symptoms or clinical signs suggestive of thyroid underfunction or overfunction, including anemia,elevated cholesterol, and hyponatremia.

6. Women with type I diabetes. 7. Women with other autoimmune disorders. 8. Women with infertility who should have screening with TSH as part of their infertility work-up. 9. Women with previous therapeutic head or neck irradiation. 10. Women with a history of miscarriage or preterm delivery.

References 1. LeBeau& Mandel.Thyroid Disorders During Pregnancy.Endocrinol Metab Clin N Am 35 (2006) 117–136. 2. Neale et al. Thyroid Disease in Pregnancy.Clin Perinatol 34 (2007) 543–557. 3. Abalovich et al. • Guideline: Thyroid Dysfunction during and after Pregnancy. J Clin Endocrinol Metab, August 2007, 92(8) (Supplement):S1–S47. 4. Kronenber: Williams Textbook of Endocrinology, 11th ed. 5. Up To Date ver.15.1